Ringing the Warning Bell: Colistin-Resistant Klebsiella

In all the latest bad news about bacteria becoming highly resistant — through carbapenem resistance, or the “Indian supergene” NDM-1 — there has been one hopeful thread: All of the organisms have remained susceptible to one very old, little-used drug called colistin.

That might be about to change. Which would be very, very bad news.

Writing in a recent issue of Clinical Infectious Diseases, faculty from the University of Pittsburgh say they saw five patients last year with colistin-resistant Klebsiella pneumoniae, a Gram-negative bacterium that is a frequent cause of very serious hospital infections and that has already become resistant to multiple classes of drugs.

The patients were seen over four months at University of Pittsburgh Medical Center. Four of them were cared for by the transplant team and the fifth was in a medical ward in a separate building. One of the patients died.

The cluster unfolded like this:

The first patient was a 63-year-old man who was hospitalized in January 2010, initially on a surgical ward, and then scheduled for a liver transplant. Ten days after being admitted, he was diagnosed with carbapenem-resistant Klebsiella or CRKP, an increasingly common drug-resistant organism (subject of my Scientific American piece last April) for which the drugs colistin and tigecycline are the only remaining treatments. He was transferred to the transplant intensive care unit, and on March 10, his Klebsiella infection was discovered to have become colistin-resistant.

Five days after that man came into the hospital, a 25-year-old woman was admitted. She was suffering from hemorrhagic pancreatitis and was scheduled for a multi-organ transplant; she went straight to the transplant unit. After she had been there two months, she was also diagnosed with CRKP, and also began receiving colistin. A month later, she also developed colistin-resistant Klebsiella – an especially stubborn infection that would keep her in the hospital for six months, until September.

The third patient changed the pattern, because he developed colistin-resistant Klebsiella even though he had never received the drug, making it likely that the resistant organism was passed to him from another patient by a health care worker or something in the hospital environment. He was 65 years old and came into the hospital’s surgical ward, the place where the first patient began treatment, in the middle of March, for a liver transplant. His colistin-resistant infection was discovered just nine days later.

The fourth patient, a 42-year-old man, also needed a liver transplant. He entered the transplant intensive care unit at the end of February, was diagnosed with CRKP in early April, got colistin, and was discovered to have colistin-resistant Klebsiella two weeks later. He stayed in the hospital until he died in late May.

Finally, the fifth patient — a 41-year-old woman with a traumatic brain injury — never went near the transplant unit. She came into the hospital’s medical ward, in a separate building, in late March, two days after the colistin-resistant infections were diagnosed in the second and third patients. She never had CRKP, and never received colistin — but in the middle of May, she was discovered to have a urinary tract infection that was colistin-resistant. She also survived.

There are a couple of observations that can be teased out of these cases.

The first is that these infections tend to happen to people who are already very sick: in need of a transplant; or having gotten a transplant, and on immune system-suppressing drugs; or with traumatic injury. They are people who would have been at risk for hospital-acquired infections.

The second is how these unexpectedly resistant hospital infections complicate the course of an already-sick patient. The victims in this outbreak were in the hospital from six weeks, in the shortest course, to six months in the longest.

The third is that some treatment is thankfully still possible. The organism — which was identical in four of the patients and negligibly different in the fifth — still responded to tigecycline, a relatively new drug. But in the table of susceptibility and resistance published in the journal, tigecycline was manifestly the only drug that still worked.

There have been other scattered reports of colistin resistance: One in Hungary, two in Greece, one in Korea — all reported last year — and a cluster of five cases in Detroit in 2009. The Pittsburgh authors say:

…Clinically selected colistin-resistant organisms, once emerged, have a potential to persist in the patients and the hospital environment and cause subsequent transmission. With the continued use of colistin for treatment of infection with various multidrug-resistant Gram-negative pathogens, it is likely that we will see an increasing number of instances of both de novo emergence of resistance and nosocomial spread.

To recap: A resistance factor is spreading that leaves very serious infections treatable by only a single remaining drug, one which is acknowledged not to be perfect. The more a drug is used, the faster resistance against it develops. Especially for Gram-negative infections, there are no new drugs in the pipeline.

It really is time to pay attention to this, before we find ourselves at the point where no drugs work at all.

Update: And here we go. Last night (Aug. 16), the Journal of Antimicrobial Chemotherapy published an advance-access letter that describes a patient infected with E. coli that was carrying NDM-1. It was susceptible to both tigecycline and colistin. The patient received tigecycline, and developed tigecycline resistance. Colistin continued to work, and the patient recovered. But now tigecycline resistance is out there, and may be circulating. Not good.